Clinical implications of pretreatment inflammatory biomarkers as independent prognostic indicators in prostate cancer.

OBJECTIVES: Research on the relationship between inflammatory biomarkers and malignant tumors has become a hotspot. Many studies have demonstrated that neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and red blood cell distribution width (RDW) could act as independent prognostic indicators for several solid tumors. This study aimed to evaluate the clinical implications of pretreatment inflammatory biomarkers, including NLR, PLR, and RDW as independent prognostic indicators in prostate cancer (PCa). METHODS: A total of 226 PCa patients who were diagnosed at our institution from 2011 to 2016 were analyzed retrospectively. We compared the clinicopathological features, survival curves, and prognosis of the PCa patients between the high and low groups according to the cutoffs of NLR, PLR, and RDW. RESULTS: The pretreatment NLR, PLR, and RDW values were significantly higher in the patients with PCa than those in the controls (P<.05). Increased NLR and PLR values were significantly associated with high risk of progression, including higher Gleason scores, cell proliferation antigen 67 (Ki-67) indexes, and prostate-specific antigen (PSA) levels (P<.05), whereas an elevated RDW was only associated with an older age. An increased NLR was correlated with both overall survival (OS) (P=.025) and disease-free survival (DFS) (P=.017). In addition, a higher PLR only showed a significantly worse DFS (P=.040). Pretreatment NLR was an independent prognostic indicator of DFS. CONCLUSIONS: The pretreatment NLR and PLR might be beneficial to predict the progression and prognosis of PCa. Furthermore, NLR was more effective than PLR acting as an independent prognostic indicator for PCa.

The red distribution width and the platelet distribution width as prognostic predictors in gastric cancer.

BACKGROUND: Increasing attention is focused on the relationship of inflammation biomarkers with malignant tumors. The purpose of the present study was to detect whether the preoperative the red distribution width (RDW) and the platelet distribution width (PDW) can be used to distinguish patients with gastric cancer (GC) or early stage GC from the healthy controls and predict the progression and prognosis of the GC. METHODS: The RDW and PDW values of 227 patients with GC and 164 patients with early GC were retrospectively analyzed comparing with 101 healthy controls. In addition, the clinicopathological features, survival curves and prognosis of the patients with GC were compared between the high and low groups according to the RDW and PDW values. RESULTS: Significant higher RDW and lower PDW were detected in patients with GC and early GC compared to the healthy controls. A higher RDW was significantly associated with older age, a larger tumor diameter, deeper tumor infiltration, and lymph node metastasis while a lower PDW was significantly associated with male, older age, a larger tumor diameter, deeper tumor infiltration, elevated CEA and CA125. Increased RDW was significantly associated with worse overall survival (OS) and disease-free survival (DFS) for GC (P = 0.042 and P = 0.033, respectively) and early GC (P = 0.037 and P = 0.009, respectively) while decreased PDW indicated a significantly association with poor DFS for early GC (P = 0.006). Univariate and multivariate survival analysis showed that RDW and PDW can act as independent prognostic factors for DFS (P = 0.028 and P = 0.020) in patients with early GC. CONCLUSION: The preoperative RDW and PDW were simple and convenient predictive factors for the progression and prognosis of patients with GC.

The diagnostic and prognostic value of haematologic parameters in multiple myeloma patients.

OBJECTIVES: Multiple myeloma (MM) is a malignant disease characterized by a single clonal proliferation of B cell-derived plasma cells in the bone marrow. It is the second most common haematologic malignancy in adults. The objective of this retrospective study is to evaluate the diagnostic and prognostic value of haematologic parameters in MM. METHODS: The difference of NLR/ALB ratio (NAR) and NLR/HDL-C ratio (NHR) between the 151 newly diagnosed MM patients and 153 healthy controls was compared. According to NAR and NHR cutoff values obtained from the ROC curve, MM patients were divided into low group and high group. The differences in hematological parameters and survival time between the two groups were compared. Independent prognostic analysis was performed using Cox proportional hazard regression model. RESULTS: The NAR and NHR values in MM group were significantly higher than those in control group (P < 0.001). Higher NAR levels were significantly associated with lower albumin (ALB), higher ß2 microglobulin(ß2-MG), higher creatinine (Crea), and highe ISS stage (All P<0.05). High NHR group was significantly correlated with age , ß2-MG and ISS stage (All P<0.05). In high NAR or NHR groups, OS and DFS was significantly shortened and the prognosis was poor (P < 0.05). Multivariate analysis showed that PLT, ISS stage and NAR were independent prognostic indicators of OS in MM patients, while ALB, PLT and NAR were independent prognostic factors of DFS. CONCLUSION: NAR and NHR are inexpensive, readily available diagnostic indicators for MM, and NAR is an independent prognostic factor for MM.

Erratum: Expression of Tim-3 in breast cancer tissue promotes tumor progression.

[This corrects the article on p. 1157 in vol. 11, PMID: 31938210.].

CCL20 mediates the anti-tumor effect of vitamin D3 in p38MAPK/NF-κB signaling in colitis-associated carcinogenesis.

Vitamin D3 is beneficial in ameliorating or preventing inflammation and carcinogenesis. CCL20 is a potential therapeutic target in carcinogenesis, which mediates the protective effect of vitamin D or vitamin D analogue in autoimmune and cancer diseases. Here we aim to evaluate whether vitamin D3 plays a protective role in colitis-associated colorectal cancer (CAC) by affecting CCL20 and the molecular mechanism. Administration of azoxymethane (AOM) followed with dextran sulfate sodium (DSS) was used to simulate CAC in mouse. After 5-day DSS treatment, vitamin D3 supplementation was for 9 weeks at 60 IU/g/w. We found that dietary vitamin D3 significantly reduced the tumor number and tumor burden in mouse. In-vivo and -vitro, vitamin D3 reduced the levels of CCL20, phospho-p38 MAPK (p-p38) and phospho-NF-κB p65 (p-p65), and the transcriptional activity of NF-κB. Further studies showed that CCL20 mediated the inhibition of vitamin D3 in p38MAPK-mediated NF-κB signaling in vitro. Taken together, vitamin D3 effectively suppressed colonic carcinogenesis in AOM-DSS mouse model. Downregulation of CCL20 may contribute to the preventive effect of vitamin D3 on NF-κB activity. It may merit further clinical investigation as a therapeutic agent against CAC in humans.

Gamma-deprotonation of anionic bis(trimethylsilyl)amidolanthanide complexes with a countered [(Tp(Me2))2Ln]+ cation.

Tp(Me2)LnCl(2) (1) reacts with 2 equiv of KN(SiMe(3))(2) in tetrahydrofuran at room temperature to yield the ligand redistribution/gamma-deprotonation products [(Tp(Me2))(2)Ln](+)[((Me(3)Si)(2)N)(2)Ln(CH(2))SiMe(2)N(SiMe(3))](-) [Ln = Er (2), Y (3)]. Complex 2 can also be obtained by reacting [(Me(3)Si)(2)N](2)ErCl with KTp(Me2). However, 1 reacts with 1.5 and 1 equiv of KN(SiMe(3))(2) to yield [(Tp(Me2))(2)Er](+)[((Me(3)Si)(2)N)(3)ErCl](-) (4) and [(Tp(Me2))(2)Er](+){[(Me(3)Si)(2)N)Tp(Me2)ErCl](2)(mu-Cl)(2)K}(-) (5), respectively. Furthermore, it is found that 2 reacts with 2 equiv of CyN=C=NCy (Cy = cyclohexyl) to give the tandem HN(SiMe(3))(2) elimination and Ln-C insertion product (Tp(Me2))Er[(CyN)(2)CCH(2)SiMe(2)N(SiMe(3))] (6) in 71% isolated yield. The results reveal that the gamma-deprotonation degree of advancement increases with an increase of the steric hindrance around the central metal ion. All new complexes have been characterized by elemental analysis and spectroscopic properties, and their solid-state structures have also been determined through single-crystal X-ray diffraction analysis.

Synthesis of mixed Cp/Tp(Me2) lanthanide complexes from lanthanocene precursors and their structures and reactivities.

Reaction of Cp(2)LnCl with 1 equiv of KTp(Me2) in toluene gives the mixed Tp(Me2)/Cp lanthanide complexes Cp(2)Ln(Tp(Me2)) (Ln = Yb (1a), Er (1b), Dy (1c)), while unexpected complexes CpLn(Tp(Me2))Cl(THF) (Ln = Yb (2a), Er (2b.THF), Dy (2c), Y (2d)) are obtained when the reactions are carried out in THF. Complex 2b can also be formed by the reaction of CpErCl(2)(THF)(3) with 1 equiv of KTp(Me2) in THF. Moreover, complex 1a can also be obtained from the reaction of Cp(3)Yb and KTp(Me2). The results not only represent an efficient and versatile method for the synthesis of mixed Cp/Tp(Me2) lanthanide complexes but also provide new insight into the reactivity of Cp(2)LnCl. Furthermore, the reactivities of complexes 1a-c toward proton-donating reagents are examined. It has been found that 1b reacts with benzotriazole (C(6)H(4)NHN(2)) in THF to yield a lanthanide metallomacrocyclic complex [(Tp(Me2))CpEr(mu-N(3)C(6)H(4))](3) (3), while the reaction of 1a with 1 equiv of 2-aminopyridine in THF gives an unexpected oxide complex [(Tp(Me2))Yb(2-HNC(5)H(4)N)](2)(mu-O) (4). Presumably, the oxide ligand of compound 4 results from adventitious water. In addition, treatment of 1c with 2 equiv of 3,5-dimethylpyrazole yields a completely Cp-abstracted product (Tp(Me2))Dy(Pz(Me2))(2)(THF) (5), which can also be directly obtained from a three-component reaction of Cp(2)DyCl, KTp(Me2), and 3,5-dimethylpyrazole in THF. These results further indicate that the new mixed Tp(Me2)/Cp lanthanide complexes are practical and versatile precursors for the synthesis of poly(pyrazolyl)borate lanthanide derivatives. All new compounds have been characterized by elemental analysis and spectroscopic methods. The structures of complexes 1a,b and 2-5 have also been determined through single-crystal X-ray diffraction analysis.

Diagnosis and survival values of neutrophil-lymphocyte ratio (NLR) and red blood cell distribution width (RDW) in esophageal cancer.

BACKGROUND: Recent studies have borne out claims that inflammation has a vital role in the development and progression of many diseases, including cancers. It has been reported that neutrophil-lymphocyte ratio (NLR) and red blood cell distribution width (RDW) could act as independent prognostic factors for several malignant tumors. We evaluated the diagnosis and prognosis values of preoperative inflammatory indicators, including NLR and RDW in esophageal cancer (EC). METHODS: We retrospectively analyzed the clinical data of 354 EC patients and 220 early esophageal cancer (EEC) undergoing potentially curative esophagectomy in Shandong Provincial Hospital Affiliated to Shandong University and chose 201 age and sex-matched healthy volunteers as the control group. We compared the clinicopathological features, survival curves and prognosis of the EC patients between the high and low groups according to the cutoff values of NLR and RDW. RESULTS: Significant higher preoperative NLR and RDW values were detected in patients with EEC and EC compared to the healthy controls (P < .001). A high RDW was significantly associated with an older age (P < .05). NLR and RDW values after surgery in EC group were significantly higher than those before surgery (P < .001 and P < .001, respectively). For EEC group, a higher RDW value showed a significantly worse overall survival (OS) and disease-free survival (DFS) (P = .040 and P = .013, respectively). For EC group, an increased NLR indicated a significantly association with poor overall survival (OS) (P = .004) and DFS (P = .001). Preoperative NLR can act as an independent prognostic indicator for EC. CONCLUSION: The preoperative NLR and RDW are convenient, practical easily measured biomarkers of clinical diagnosis and prognostic assessment of patients with EC. Furthermore, NLR was more effective than RDW acting as an independent prognostic biomarker for EC.

Facile construction of a novel aminoquinazolinate anionic ligand through organolanthanide-mediated intermolecular nucleophilic addition/cyclization of anthranilonitrile.

Compounds Cp 2Ln[kappa (3)-(4-NH(C 8N 2H 4)(2-NH 2C 6H 4)] [Cp = C 5H 5; Ln = Er ( 1), Y ( 2)] were synthesized by the reaction of Cp 2LnN (i) Pr 2(THF) with anthranilonitrile, indicating a novel organolanthanide-mediated intermolecular nucleophilic addition/cyclization of anthranilonitrile. To trap the intermediate I, a probe reaction of Cp 2ErN (i) Pr 2(THF) with anthranilonitrile and carbodiimide has also been investigated.

Expression of Tim-3 in breast cancer tissue promotes tumor progression.

T-cell immunoglobulin mucin-3 (Tim-3) plays a pivotal role in immune regulation and tolerance induction as a negative regulatory molecule on innate versus adaptive immune cells, especially in antitumor immunity. However, the mechanism of Tim-3 expression on tumor cells and the mechanism that inhibits anti-tumor immunity are obscure. In this present study, we aimed to investigate the functions of Tim-3 in breast cancer and to explore its correlation to tumor prognosis. In a total of 42 clinical samples of invasive breast cancer, Tim-3 was semiquantitatively scored based on both distribution and intensity of immunohistochemistry staining and was found to correlate with clinicopathological parameters. Western blotting was used to detect the expression of Tim-3 in breast cancer cells. Furthermore, the effect of Tim-3 in breast cancer cells was evaluated after overexpression by ADV-Tim-3 and downregulation by Tim-3-siRNA. High immunoreactivity of Tim-3 was found to be significantly correlated with clinical stage, metastasis, KI67, and a lower 5-year survival rate. We supported this finding by confirming the presence of Tim-3 protein in the breast cell lines. Downregulation of Tim-3 significantly inhibited the proliferation, migration, and invasion of breast cancer cells while it promoted apoptosis. Overexpression of Tim-3 promoted the proliferation, migration, and invasion of breast cancer cells and inhibited apoptosis. Taken together, as a valuable marker of breast cancer prognosis, Tim-3 in breast cancer cells play an important role in the progression of breast cancer and may be an effective novel target in tumor prevention and treatment.

Clinical value of the preoperative neutrophil-to-lymphocyte ratio and red blood cell distribution width in patients with colorectal carcinoma.

The aim of the present study was to investigate the clinical value of the preoperative neutrophil-to-lymphocyte ratio (NLR) and red blood cell distribution width (RDW) in the peripheral blood of colorectal carcinoma (CRC) patients. Clinical data obtained from 240 patients with CRC undergoing radical surgical resection in Shandong Provincial Hospital Affiliated to Shandong University (Jinan, Shandong, China) between January 2011 and April 2015 were retrospectively analyzed. Data were also collected from 110 patients with colon polyps and 48 healthy volunteers to serve as controls for comparative analysis. The clinicopathological characteristics of the patients in the low and high NLR and RDW groups were compared. The NLR and RDW values were compared prior to and following surgery. Kaplan-Meier analyses and Cox regression modeling were performed to predict overall survival (OS) and disease-free survival (DFS). The NLR and RDW levels in the CRC patients were markedly higher than those in the colon polyp patients and the healthy controls. The optimum NLR and RDW cutoff points for CRC were 2.06 and 13.45%, respectively. Significant differences were detected in tumor location, diameter, degree of differentiation, tumor depth, carcinoembryonic antigen and carbohydrate antigen 199 when comparing the high and low NLR groups (P<0.05). A high RDW was significantly associated with distant metastasis and older age in CRC patients. No significant difference was detected in the NLR and RDW levels of CRC patients prior to and following surgery (P>0.05). CRC patients with an increased RDW had significantly worse OS and DFS rates, particularly those with metastatic CRC (P<0.05). Patients with a high NLR exhibited a reduced DFS time in CRC (P=0.053), although this difference was not significant, and a significantly worse DFS time in metastatic CRC (P=0.047). In conclusion, it is convenient to use preoperative NLR and RDW to predict prognosis following surgery for patients with CRC.

T Cell Immunoglobulin- and Mucin-Domain-Containing Molecule 3 Gene Polymorphisms and Susceptibility to Invasive Breast Cancer.

The T-cell immunoglobulin and mucin domain containing molecule 3 (TIM-3) gene is an important immune regulatory molecule. In fact, studies have shown that polymorphisms in the (TIM-3) gene may be associated with various cancers. The goal of this study was to investigate whether the -1516G/T, -574G/T, or +4259T/G single-nucleotide polymorphisms (SNPs) in the TIM-3 gene contribute to a genetic susceptibility to invasive breast cancer in the Han ethnicity of northern China. Genotyping of the TIM-3 -1516G/T, -574G/T and +4259T/G were performed in 301 patients with invasive breast cancer and in 151 healthy individuals via a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The results showed that the prevalence of the +4259T/G genotype and the +4259G allele were significantly increased in the breast cancer patients compared to the controls [odds ratio (OR)=7.641, 95% confidence interval (CI), 1.795-32.522, P=0.001; OR=7.317, 95%CI, 1.731-30.925, P=0.001, respectively]. The GGG haplotype had a significantly different distribution between patients and controls (OR=5.421, 95%CI, 1.263-23.275, P=0.011). In addition, the prevalence of the +4259T/G polymorphism was higher in patients with metastasis than those without metastasis (13.6% vs. 4.8%, respectively, OR=3.158, 95%CI, 1.300-7.672, P=0.011). Furthermore, results showed that the prevalence of the +4259T/G genotype was correlated with the intensity of Ki-67 by immunohistochemical staining (P=0.022). Overall, these results suggested that the +4259T/G SNP in the TIM-3 gene may play an important role as a genetic risk factor for the progression and prognosis of invasive breast cancer in these patients. in Han ethnicity of northern China.

Investigation of T-cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) polymorphisms in essential thrombocythaemia (ET).

OBJECTIVES: T-cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) is preferentially expressed on terminally differentiated Th1 cells and inhibits their IFN-γ production. It has been reported that chronic inflammation may be an important driving force for myeloproliferative neoplasms (MPNs). Therefore, we hypothesized that as an important inflammation regulator, TIM-3 may be involved in essential thrombocythaemia (ET). The goal of this study was to investigate whether the -1516G > T, -574G > T and +4259T > G single-nucleotide polymorphisms (SNPs) within the TIM-3 gene contribute to the genetic susceptibility of individuals to ET. METHODS: Genotyping of the TIM-3 -1516G > T, -574G > T and + 4259T > G SNPs was performed in 175 patients with ET and in 151 controls via a polymerase chain reaction-restriction fragment length polymorphism assay. We also investigated the relationships between the genotypes of each SNP and the risk factors of ET such as routine blood indexes, age and JAK2 V617F mutation. RESULTS: The genotype and allele frequencies of the -1516G > T SNP (p = 0.016 and 0.019, respectively), the -574G > T SNP (p = 0.035 and 0.038, respectively) and the +4259T > G SNP (p = 0.036 and 0.038, respectively) of the ET patients and the controls were significantly different. A haplotype analysis found that the GGT and TGT haplotypes had significantly different distributions between ET and controls (p = 0.041 and 0.041, respectively). However, no significant differences were detected between the genotypes of all SNPs and routine blood indexes, age and JAK2V617F mutation. CONCLUSION: The -1516G > T, -574G > T and +4259T > G SNPs within TIM-3 gene might play an important role as a genetic risk factor in the pathogenesis of ET.

Synthesis and structures of titanium and yttrium complexes with N,N'-tetramethylguanidinate ligands: different reactivity of the M-N bonds toward phenyl isocyanate.

A salt elimination reaction of bis(cyclopentadienyl)titanium dichloride (C(5)H(5))(2)TiCl(2) with one equiv. of N,N'-tetramethylguanidinate lithium [LiN[double bond, length as m-dash]C(NMe(2))(2)] proceeded in THF at room temperature to yield a bis(cyclopentadienyl)titanium mono-guanidinate chloride (C(5)H(5))(2)TiCl(N[double bond, length as m-dash]C(NMe(2))(2)) (). However, treatment of two equiv. of LiN[double bond, length as m-dash]C(NMe(2))(2) with (C(5)H(5))(2)TiCl(2) under the same conditions resulted in the elimination of one cyclopentadienyl ring to form an unexpected mono(cyclopentadienyl)titanium bis(guanidinate) chloride (C(5)H(5))TiCl[N[double bond, length as m-dash]C(NMe(2))(2)](2) (), in which only one Ti-Cl bond is broken, with the other Ti-Cl bond retained. Reaction of [(C(5)H(5))(2)YCl](2) with LiN[double bond, length as m-dash]C(NMe(2))(2) gave the corresponding product {(C(5)H(5))(2)Y[mu-eta(1):eta(2)-N[double bond, length as m-dash]C(NMe(2))(2)]}(2) (). On further investigations on the reactivity of toward phenyl isocyanate, we found phenyl isocyanate only inserts into the Y-N(mu-Gua) bonds of to yield [(C(5)H(5))(2)Y(mu-eta(1):eta(2)-OC(N[double bond, length as m-dash]C(NMe(2))(2))NPh)](2) (). Complexes were characterized by elemental analysis and spectroscopic properties and their solid-state structures were determined by X-ray single-crystal diffraction.